Mapping Dark Matter in the Milky Way using Normalizing Flows and Gaia DR3

We present a novel, data-driven analysis of Galactic dynamics, using unsupervised machine learning -- in the form of density estimation with normalizing flows -- to learn the underlying phase space distribution of 6 million nearby stars from the Gaia DR3 catalog. Solving the collisionless Boltzmann equation with the assumption of approximate equilibrium, we calculate -- for the first time ever -- a model-free, unbinned, fully 3D map of the local acceleration and mass density fields within a 3 kpc sphere around the Sun. As our approach makes no assumptions about symmetries, we can test for signs of disequilibrium in our results. We find our results are consistent with equilibrium at the 10% level, limited by the current precision of the normalizing flows. After subtracting the known contribution of stars and gas from the calculated mass density, we find clear evidence for dark matter throughout the analyzed volume. Assuming spherical symmetry and averaging mass density measurements, we find a local dark matter density of $0.47\pm 0.05\;\mathrm{GeV/cm}^3$. We fit our results to a generalized NFW, and find a profile broadly consistent with other recent analyses.Comment: 19 pages, 13 figures, 3 table

Percutaneous reduction and fixation of an intra-articular calcaneal fracture using an inflatable bone tamp: description of a novel and safe technique

Calcaneal fractures are common injuries involving the hind foot and often a source of significant long-term morbidity. Treatment options have changed throughout the ages from periods of preferred nonoperative management to closed reduction with a mallet, and more recently, open reduction and anatomic internal fixation. The current treatment of choice; however, is often debated, as open management of these fractures carries many risks to include wound breakdown and infection. A less invasive form of surgical management through small incisions, while maintaining the ability to obtain joint congruency, anatomic alignment, and restore calcaneal height and width would be ideal. We propose a novel form of fracture reduction using an inflatable bone tamp and percutaneous fracture fixation. Preoperative planning and experienced fluoroscopy is crucial to successful management using this method. Although we achieved successful radiographic outcome in this case, long-term functional outcome of this technique are yet to be published

GalaxyFlow: Upsampling Hydrodynamical Simulations for Realistic Gaia Mock Catalogs

Cosmological N-body simulations of galaxies operate at the level of "star particles" with a mass resolution on the scale of thousands of solar masses. Turning these simulations into stellar mock catalogs requires "upsampling" the star particles into individual stars following the same phase-space density. In this paper, we demonstrate that normalizing flows provide a viable upsampling method that greatly improves on conventionally-used kernel smoothing algorithms such as EnBiD. We demonstrate our flow-based upsampling technique, dubbed GalaxyFlow, on a neighborhood of the Solar location in two simulated galaxies: Auriga 6 and h277. By eye, GalaxyFlow produces stellar distributions that are smoother than EnBiD-based methods and more closely match the Gaia DR3 catalog. For a quantitative comparison of generative model performance, we introduce a novel multi-model classifier test. Using this classifier test, we show that GalaxyFlow more accurately estimates the density of the underlying star particles than previous methods.Comment: 17 pages, 11 figure

Colon polyps in patients with short bowel syndrome before and after teduglutide: post hoc analysis of the STEPS study series

Background & aims: Teduglutide promotes intestinal growth and is approved for the treatment of short bowel syndrome and intestinal failure (SBS-IF). Based on the pharmacologic activity and preclinical findings, teduglutide can potentially induce proliferative colonic mucosal changes. The aim of this study is to report the occurrence of colorectal polyps in adult patients with SBS-IF who received teduglutide in clinical studies conducted to date. Methods: A post hoc analysis of the completed Study of Teduglutide Effectiveness in Parenteral Nutrition-Dependent Short Bowel Syndrome Subjects (STEPS) clinical study series (NCT00798967, EudraCT 2008-006193-15; NCT00930644, EudraCT 2009-011679-65; NCT01560403) evaluated electronic case report form data for baseline colonoscopies (performed before treatment) and for surveillance or end-of-study (performed after treatment with teduglutide 0.05 mg/kg/day for 24 and 36 months) post-exposure procedures. Results: In the STEPS studies, 73 patients treated with teduglutide had a baseline colonoscopy. No post-exposure colonoscopy was scheduled in STEPS. In STEPS-2/3, 50 of 65 patients with remnant colon (77%) underwent a protocol-mandated post-exposure colonoscopy. Colon polyps were reported at baseline in 12% (9/73) of patients and post-exposure in 18% (9/50) of patients. Two had polyps both at baseline and post-exposure. On histology, available for 7 patients, 5 had adenomas (1 serrated, 4 tubular) and none had malignancy or high-grade dysplasia. Conclusion: These data support recommendations for colonoscopic screening before teduglutide therapy and subsequent on-therapy colonoscopic surveillance for patients with SBS-IF. Further studies are required to assess the risk of polyp formation in patients with SBS-IF and the most appropriate colon polyp surveillance strategies

Molecular Basis for Integrin Adhesion Receptor Binding to p21-activated kinase 4 (PAK4)

Integrin adhesion receptors provide links between extracellular ligands and cytoplasmic signaling. Multiple kinases have been found to directly engage with integrin β tails, but the molecular basis for these interactions remain unknown. Here, we assess the interaction between the kinase domain of p21-activated kinase 4 (PAK4) and the cytoplasmic tail of integrin β5. We determine three crystal structures of PAK4-β5 integrin complexes and identify the PAK-binding site. This is a region in the membrane-proximal half of the β5 tail and confirmed by site-directed mutagenesis. The β5 tail engages the kinase substrate-binding groove and positions the non-phosphorylatable integrin residue Glu767 at the phosphoacceptor site. Consistent with this, integrin β5 is poorly phosphorylated by PAK4, and in keeping with its ability to occlude the substrate-binding site, weakly inhibits kinase activity. These findings demonstrate the molecular basis for β5 integrin-PAK4 interactions but suggest modifications in understanding the potential cellular role of this interaction

Profiling of Substrate Specificities of 3C-Like Proteases from Group 1, 2a, 2b, and 3 Coronaviruses

BACKGROUND: Coronaviruses (CoVs) can be classified into alphacoronavirus (group 1), betacoronavirus (group 2), and gammacoronavirus (group 3) based on diversity of the protein sequences. Their 3C-like protease (3CL(pro)), which catalyzes the proteolytic processing of the polyproteins for viral replication, is a potential target for anti-coronaviral infection. METHODOLOGY/PRINCIPAL FINDINGS: Here, we profiled the substrate specificities of 3CL(pro) from human CoV NL63 (group 1), human CoV OC43 (group 2a), severe acute respiratory syndrome coronavirus (SARS-CoV) (group 2b) and infectious bronchitis virus (IBV) (group 3), by measuring their activity against a substrate library of 19 × 8 of variants with single substitutions at P5 to P3' positions. The results were correlated with structural properties like side chain volume, hydrophobicity, and secondary structure propensities of substituting residues. All 3CL(pro) prefer Gln at P1 position, Leu at P2 position, basic residues at P3 position, small hydrophobic residues at P4 position, and small residues at P1' and P2' positions. Despite 3CL(pro) from different groups of CoVs share many similarities in substrate specificities, differences in substrate specificities were observed at P4 positions, with IBV 3CL(pro) prefers P4-Pro and SARS-CoV 3CL(pro) prefers P4-Val. By combining the most favorable residues at P3 to P5 positions, we identified super-active substrate sequences 'VARLQ↓SGF' that can be cleaved efficiently by all 3CL(pro) with relative activity of 1.7 to 3.2, and 'VPRLQ↓SGF' that can be cleaved specifically by IBV 3CL(pro) with relative activity of 4.3. CONCLUSIONS/SIGNIFICANCE: The comprehensive substrate specificities of 3CL(pro) from each of the group 1, 2a, 2b, and 3 CoVs have been profiled in this study, which may provide insights into a rational design of broad-spectrum peptidomimetic inhibitors targeting the proteases